Valz Combi, 5 mg+80 mg 28 pcs

Pharmacotherapeutic group: combined hypotensive agent (BMCC + angiotensin II receptor antagonist)

ATX code: C09DB01

Pharmacological Properties

.Pharmacological action

The pharmacological action is antihypertensive.

Pharmacodynamics

The drug Valz Combi is a combination of two antihypertensive components with a complementary mechanism of blood pressure (BP) control. Amlodipine, a dihydropyridine derivative, belongs to the class of “slow” calcium channel blockers (CMCCB), and valsartan belongs to the class of angiotensin II receptor antagonists (ARA II). The combination of these components has a mutually complementary antihypertensive effect, which leads to a more pronounced BP reduction compared to that when they are used separately.

Amlodipine

Amlodipine in the drug inhibits transmembrane entry of calcium ions into cardiomyocytes and vascular smooth muscle cells. Mechanism of antihypertensive action of amlodipine is related to direct relaxant effect on vascular smooth muscle which causes decrease of total peripheral vascular resistance (TPR) and blood pressure.

After therapeutic doses in patients with arterial hypertension, amlodipine causes vasodilation leading to a decrease in BP (in the patient “lying” and “standing” position). The BP reduction is not accompanied by significant changes in heart rate (HR) and catecholamine levels with long-term use.

In arterial hypertension patients with normal renal function, amlodipine at therapeutic doses decreases renal vascular resistance, increases glomerular filtration rate (GFR) and improves renal blood flow without changing filtration fraction and degree of proteinuria.

Amlodipine decreases BP in therapeutic dose range without negative inotropic effect even with concomitant use with beta-adrenoblockers.

Amlodipine does not alter sinoatrial node function or atrioventricular conduction. When using amlodipine in combination with beta-adrenoblockers in patients with arterial hypertension or angina pectoris, BP reduction is not accompanied by adverse electrocardiogram changes.

The clinical efficacy of amlodipine has been proven in patients with chronic stable angina pectoris, vasospastic angina pectoris, and angiographically confirmed coronary artery disease.

Valsartan

Valsartan is an active and specific angiotensin II receptor antagonist for oral administration. It acts selectively on AT₁ subtype receptors, which are responsible for pressor and several other effects of angiotensin II.

Valsartan does not inhibit angiotensin-converting enzyme (ACE), also known as kininase II, which converts angiotensin I to angiotensin II and causes bradykinin breakdown.

The use of angiotensin II antagonists does not inhibit ACE and accumulation of bradykinin or Substance P, so the development of dry cough is unlikely.

Valsartan does not interact with or block other hormone receptors or ion channels important to the regulation of cardiovascular function.

When treating patients with arterial hypertension with valsartan, there is a decrease in BP with no change in HR.

The antihypertensive effect of the drug is seen within 2 hours in most patients after a single dose of valsartan. Maximal BP decrease develops in 4-6 hours. The effect of the drug lasts more than 24 hours. With repeated use, maximum BP reduction, regardless of the dose taken, is usually achieved within 2-4 weeks and is maintained during prolonged therapy. Abrupt discontinuation of valsartan is not associated with withdrawal syndrome (severe increase in BP or other adverse clinical effects). The use of valsartan in patients with chronic heart failure (CHF) (NYHA class II-IV) leads to a significant reduction in hospitalizations for CHF. When taking valsartan in patients with left ventricular failure (stable clinical course) or with impaired LV function after myocardial infarction, there is a decrease in cardiovascular mortality.

Amlodipine + Valsartan

The combination of amlodipine and valsartan reduces BP in a dose-dependent manner over the therapeutic dose range. After a single dose of amlodipine + valsartan combination, the antihypertensive effect persists for 24 hours.

A sudden discontinuation of the drug is not accompanied by a sharp increase in BP (no withdrawal syndrome).

Therapeutic efficacy is independent of the patient’s age, sex, race and body mass index.

In combination therapy of amlodipine + valsartan, comparable BP control is achieved with lower likelihood of peripheral edema in patients with previously achieved BP control and significant peripheral edema on amlodipine therapy.

Pharmacokinetics

The pharmacokinetics of amlodipine + valsartan combination therapy are linear.

Amlodipine

Intake

. After oral administration of amlodipine at therapeutic doses, its maximum plasma concentration (C_max) is reached after 6-12 hours. The value of absolute bioavailability is on average 64-80%. Food intake does not affect the bioavailability of amlodipine.

Distribution

The volume of distribution (V_d) is approximately 21 l/kg. In vitro studies have shown that in patients with arterial hypertension approximately 97.5% of circulating amlodipine is bound to plasma proteins.

Metabolism

Amlodipine is extensively (approximately 90%) metabolized in the liver to form active metabolites.

Elimation

Elimination of amlodipine from plasma is biphasic with a half-life (T_1/2) of approximately 30 to 50 hours. Equilibrium plasma concentrations are reached after 7-8 days of use. 10% of unchanged amlodipine and 60% of amlodipine as metabolites are excreted by the kidneys.

Valsartan

Absorption

. After oral administration, valsartan C_max in plasma is reached within 2-4 h. Mean absolute bioavailability is 23%. When valsartan is taken with food, there is a 40% decrease in bioavailability (as measured by the area under the pharmacokinetic concentration-time curve (AUC)) and C_max in plasma by almost 50%, although approximately 8 hours after taking the drug, plasma concentrations of valsartan in the dietary intake group and the fasting group equalize. Decrease of AUC however is not associated with clinically significant decrease of therapeutic effect, therefore, valsartan can be prescribed regardless of the time of ingestion.

Distribution

The V_d of valsartan in equilibrium after intravenous (IV) administration is approximately 17 liters, indicating that there is no extensive distribution of the drug in tissues. Valsartan is largely bound to serum proteins (94-97%), predominantly to albumin.

Metabolism

Valsartan does not undergo marked metabolism (about 20% of the dose taken is determined as metabolites). The hydroxyl metabolite is determined in plasma at low concentrations (less than 10% of the AUC of valsartan). This metabolite is pharmacologically inactive.

Elimation

The pharmacokinetic curve of valsartan has a descending multiexponential character (T1/2α < 1 h and T1/2β, about 9 h). Valsartan is mainly excreted unchanged via the intestine (about 83% of the dose) and the kidneys (about 13% of the dose). After intravenous administration, plasma clearance of valsartan is about 2 l/h, renal clearance is 0.62 l/h (about 30% of total clearance). T_1/2 valsartan is 6 h.

Amlodipine + Valsartan

After oral administration of Valz Combi (amlodipine + valsartan), C_max of valsartan and amlodipine are reached after 3 and 6-8 h, respectively. The rate and extent of drug absorption are equivalent to the bioavailability of valsartan and amlodipine when each is taken as separate tablets.

Pharmacokinetics in Special Clinical Cases

Childhood

Pharmacokinetic features of amlodipine + valsartan combination drug use in children under 18 years of age have not been established.

Elderly patients(>65 years)

. The time to reach C_max of amlodipine in plasma in young and elderly patients is the same. Amlodipine clearance is slightly decreased in elderly patients, resulting in increased AUC and T_1/2.

The systemic effects of valsartan were slightly more pronounced in elderly patients than in younger patients, but these rates were not clinically significant. Because tolerability of the drug components was equally good in elderly and younger patients, the usual dosing regimens are recommended.

Patients with impaired renal function

In patients with impaired renal function the pharmacokinetic parameters of amlodipine do not change significantly. No correlation has been found between renal function (creatinine clearance (CK)) and systemic exposure to valsartan (AUC) in patients with varying degrees of renal impairment. No change in starting dose is required in patients with initial and moderate renal dysfunction (CK 30-50 ml/min).

Patients with impaired hepatic function

Patients with impaired hepatic function have decreased clearance of amlodipine, resulting in an increase in AUC of approximately 40-60%. On average, patients with mild (5-6 Child-Pugh scores) and moderate (7-9 Child-Pugh scores) chronic liver disease have twice the bioavailability (according to AUC) of valsartan compared to healthy volunteers (corresponding age, sex, and body weight). The drug should be used with caution in patients with hepatic dysfunction, obstructive biliary tract disease.

Indications

Active ingredient

How to take, the dosage

Overly, with a small amount of water, once a day regardless of the time of meals.

The recommended daily dose is 1 tablet containing amlodipine + valsartan at a dose of 5 mg + 80 mg, 5 mg +160 mg or 10 mg + 160 mg.
It is recommended that the drug be started with a dose of 5 mg + 80 mg once daily. The dose can be increased 1-2 weeks after the start of therapy. In patients whose BP cannot be adequately controlled, the daily dose can be gradually increased under medical supervision: Recommended maximum daily dose (for amlodipine) is 10 mg + 160 mg; maximum daily dose: 10 mg + 320 mg (2 tablets of Valz Combi in dosage of 5 mg + 160 mg once daily).

In elderly patients (> 65 years) and in patients with hepatic dysfunction or liver disease without cholestasis, reduction of the starting dose of the drug to the lowest dose of amlodipine is possible, i.e. 1 tablet containing a combination of amlodipine + valsartan at a dose of 5 mg + 80 mg or 5 mg + 160 mg.

In patients with mild to moderate renal dysfunction (CK > 30 ml/min), no adjustment of the starting dose is required.

Interaction

Amlodipine

.Other hypotensive and antianginal drugs

Amlodipine may be safely used to treat arterial hypertension with thiazide diuretics, beta-adrenoblockers or ACE inhibitors.

In patients with stable angina pectoris, amlodipine may be used in combination with other antianginal agents, e.g., long- or short-acting nitrates, beta-adrenoblockers.

The antianginal and antihypertensive effects of DMARDs may be enhanced when used in combination with thiazide and loop diuretics, ACE inhibitors, beta-adrenoblockers and nitrates.

Ethanol, barbiturates, neuroleptics, antidepressants, narcotic analgesics, means for general anesthesia

Special Instructions

Aortic stenosis / mitral stenosis / hypertrophic obstructive cardiomyopathy

. The amlodipine + valsartan combination drug has vasodilatory effects; the drug should be used with caution in patients with aortic stenosis, mitral stenosis, or hypertrophic obstructive cardiomyopathy. In patients with left ventricular outflow tract obstruction (e.g., severe aortic stenosis) the use of the drug is not recommended.

Amlodipine

Cardiovascular disease

The efficacy and safety of amlodipine in hypertensive crisis have not been established.

In acute myocardial infarction, amlodipine may be used only after hemodynamic stabilization.

In rare cases, patients with coronary heart disease (especially with severe obstructive coronary artery disease) have reported an increase in frequency, duration and/or severity of angina attacks after initiation of BMCC or after increasing their dosage.

While in general BMCC should be used with caution in patients with CHF, amlodipine in short- and long-term clinical studies did not increase mortality or the incidence of cardiovascular complications in patients with CHF. Against the background of amlodipine use in patients with CHF (NYHA functional class III and IV) of non-ischemic genesis, an increased incidence of pulmonary edema was observed, despite the absence of signs of progression of heart failure.

withdrawal syndrome

While there is no withdrawal syndrome in BMCC, it is advisable to discontinue amlodipine treatment by gradually reducing the dose of the drug. Amlodipine does not prevent abrupt withdrawal from beta-adrenoblockers.

Peripheral edema

Mild to moderate peripheral edema was the most common adverse event of amlodipine in clinical trials. The incidence of peripheral edema increased with increasing dose (with amlodipine 2.5 mg, 5 mg and 10 mg daily edema occurred in 1.8%, 3% and 10.8% of patients, respectively). Peripheral edema associated with amlodipine should be carefully differentiated from symptoms of progression of left ventricular heart failure.

Hepatic dysfunction

There have been no controlled studies in patients with impaired liver function. Increased T1/2 amlodipine has been noted in a small number of patients with mild to moderate hepatic impairment. Patients with hepatic impairment should be under medical supervision if amlodipine should be used. In some cases (e.g., in moderate hepatic insufficiency) a lower initial dose of amlodipine (2.5 mg daily) is recommended.

Elderly age

In elderly patients, T1/2 and amlodipine clearance may increase and decrease. In clinical trials, the incidence of adverse events in patients aged >65 years was approximately 6% higher than in younger patients. No change in amlodipine doses is required, but closer monitoring of patients in this category is necessary.

Other

Body weight and table salt intake should be controlled during amlodipine therapy and an appropriate diet should be prescribed.

It is necessary to maintain dental hygiene and see a dentist (to prevent soreness, bleeding and gum hyperplasia).

Valsartan

.p> Kidney function impairment

. There is no experience with the safe use of valsartan in patients with a CKR less than 10 mL/min and in patients on hemodialysis, so valsartan should be used with caution in these patients. No dose adjustment is required in patients with a CKR greater than 10 mL/min.

Hepatic impairment

Valsartan should be used with caution in patients with mild to moderate hepatic impairment without cholestasis.

Hyperkalemia

. Caution should be exercised when using valsartan concomitantly with potassium supplements, potassium-saving diuretics, potassium-containing salt substitutes, or other drugs that may cause increased blood potassium concentrations (e.g., heparin) and regular monitoring of blood potassium.

Bilateral renal artery stenosis or artery stenosis of the single kidney

. Short-course administration of valsartan in patients with renovascular hypertension secondary to unilateral renal artery stenosis does not result in any significant change in renal hemodynamics, serum creatinine or blood urea nitrogen. However, given that other drugs affecting the RAAS may cause increased serum urea and creatinine concentrations in patients with bilateral renal artery stenosis or artery stenosis of the uniciliary artery, monitoring of these parameters is recommended as a precautionary measure.

Primary hyperaldosteronism

. Valsartan is not effective for the treatment of arterial hypertension in patients with primary hyperaldosteronism because there is no activation of the RAAS in this patient population.

Kidney transplantation

There are no data on the safety of valsartan in patients undergoing kidney transplantation.

Sodium deficiency and/or decreased BOD

. In patients with significant BOD deficit, e.g., those receiving high doses of diuretics, arterial hypotension accompanied by clinical manifestations may rarely develop at the start of treatment with the drug. Prior to initiating valsartan treatment, sodium should be corrected and/or the BOD should be replenished, including by reducing the dose of the diuretic.

Angioneurotic edema, including Quincke’s edema

. Angioneurotic edema, including laryngeal and vocal cord edema resulting in airway obstruction and/or facial, lip, pharyngeal, and/or tongue edema, has occurred in patients receiving valsartan, some of these patients have previously experienced angioedema while taking other drugs, including ACE inhibitors. Valsartan should be discontinued immediately if angioedema develops and valsartan should not be restarted.

CRC/post-myocardial infarction

. In patients with CHF or after myocardial infarction who start valsartan therapy, there is often a slight decrease in BP, and therefore it is recommended that BP be controlled at the start of therapy. There is usually no need to discontinue valsartan due to hypotension if the dosing guidelines are followed. Evaluation of patients with CHF should include evaluation of renal function.

In some patients, renal function may be impaired due to inhibition of the RAAS system. In patients with CHF of III-IV functional class according to NYHA classification, whose renal function depends on the state of RAH, treatment with ACE inhibitors and ARA II may be accompanied by oliguria and/or azotemia increase and in rare cases by development of acute renal failure and/or lethal outcome. Therefore, renal function should be assessed in these categories of patients prior to the use of valsartan and periodically during treatment with the drug.

Combination therapy in arterial hypertension

In arterial hypertension, valsartan may be used in monotherapy as well as in combination with other hypotensive agents, particularly diuretics.

Combination therapy in the aftermath of myocardial infarction

. Valsartan may be used in combination with other medications used after myocardial infarction, namely thrombolytics, acetylsalicylic acid as an antiplatelet agent, beta-adrenoblockers and HMG-CoA reductase inhibitors. In this patient population, concomitant use of valsartan with ACE inhibitors is not recommended because this combination therapy has no advantage over valsartan or ACE inhibitor monotherapy with respect to overall mortality rates from any cause.

Combination therapy in CHF

. In CHF, valsartan may be used both in monotherapy and concomitantly with other agents – diuretics, cardiac glycosides, and ACE inhibitors or beta-adrenoblockers.

The use of triple combination therapy with ACE inhibitors, beta-adrenoblockers and valsartan is not recommended in this patient population.

Double RAAS blockade

. Significant decreases in BP, syncope, stroke, hyperkalemia, and renal dysfunction (including acute renal failure) have been reported in sensitive patients when treated with drugs that affect the RAAS, especially when combined. Caution is required when combining ARA II, including valsartan, with other drugs that block the RAAS, such as ACE inhibitors or aliskiren.

The concomitant use of APA II with drugs containing aliskiren is contraindicated in patients with diabetes mellitus and/or with moderate to severe renal impairment (FFR less than 60 ml/min/1.73 m2 body surface area) and is not recommended in other patients.

The concomitant use of ARA II with ACE inhibitors is contraindicated in patients with diabetic nephropathy and is not recommended in other patients.

Effects on the ability to operate vehicles and machinery

There are no data on the effect of Valz Combi on the ability to operate vehicles and machinery.

Because of possible dizziness or increased fatigue, caution should be exercised when driving or operating machinery.

Synopsis

Contraindications

Side effects

The safety of amlodipine + valsartan combination has been evaluated in over 2613 patients.

Unwanted adverse reactions are presented by systemic organ class according to the MedDRA classification and with frequency of occurrence: Very common (≥ 1/10); common (≥ 1/100 < 1/10); infrequent (≥ 1/1000 < 1/100); rare (≥ 1/10000 < 1/1000); very rare (< 1/10000), frequency unknown (cannot be estimated from available data).

Within each group separated by frequency of occurrence, adverse reactions are ranked in decreasing order of importance.

Amlodipine + valsartan

Infectious and parasitic diseases: often – nasopharyngitis, influenza.

Disorders of the immune system: frequently – hypersensitivity.

Disorders of the metabolism and nutrition: frequent – hypokalemia; infrequent – anorexia, hypercalcemia, hyperlipidemia, hyperuricemia, hyponatremia.

Mental disorders: rarely – anxiety.

Nervous system disorders: frequent – headache; infrequent – coordination disorders, dizziness, somnolence, postural vertigo, paresthesias.

VIight organ disorders: infrequently – visual impairment; rarely – visual impairment.

Hearing organ disorders and labyrinth disorders: infrequent – vertigo; rarely – tinnitus.

Cardiac disorders: infrequent – tachycardia, palpitations; rarely – syncope.

vascular disorders: infrequent – orthostatic hypotension; rarely – marked BP decrease.

Disorders of the respiratory system, thorax and mediastinum: infrequently – cough, pain in the pharynx and larynx.

Disorders of the digestive system: infrequently – diarrhea, nausea, abdominal pain, constipation, dry oral mucosa.

Skin and subcutaneous tissue disorders: infrequent – erythema, skin rash; rarely – exanthema, hyperhidrosis, itching.

Muscular and connective tissue disorders: infrequent – joint swelling, back pain, arthralgia; rarely – muscle cramps and feeling of heaviness throughout the body.

Recreational and urinary tract disorders: frequently – pollakiuria, polyuria.

Gender and mammary gland disorders: frequently – erectile dysfunction.

General disorders: often – pastosity, facial edema, asthenia, peripheral edema, increased fatigue, “rushes” of blood to the face, asthenia, fever.

In comparative and placebo-controlled clinical trials, the incidence of peripheral edema was lower in patients receiving a combination of amlodipine with valsartan (5.8%) than in patients receiving amlodipine monotherapy (9%).

Laboratory and instrumental findings: Elevated blood urea nitrogen concentrations (greater than 3.1 mmol/L) were observed slightly more frequently in the groups receiving amlodipine + valsartan (5.5%) and valsartan as monotherapy (5.5%) compared with the group receiving placebo (4.5%).

The adverse events (AEs) specific to each component may occur with Valz Combi even if they have not been observed in clinical trials.

Amlodipine

Blood and lymphatic system disorders: very rarely – leukopenia, thrombocytopenia.

Disorders of the immune system: very rarely – hypersensitivity.

Disorders of the metabolism and nutrition: very rarely – hyperglycemia.

Mental disorders: frequently – depression, insomnia/sleep disorders, mood swings; rarely – confusion.

Nervous system disorders: frequent – dizziness, headache, somnolence; infrequent – taste disorder, paraesthesia, fainting, tremor, hypoesthesia; very rare – muscle hypertonicity, peripheral neuropathy, neuropathy; frequency unknown – extrapyramidal symptoms.

Visual disorders: infrequently – deterioration of vision, visual impairment.

Cardiac disorders: often – feeling of palpitations; very rare – arrhythmias (including bradycardia, ventricular tachycardia, atrial fibrillation), myocardial infarction.

Vascular disorders: frequently – “rushes” of blood to the skin of the face; infrequently – marked decrease in BP; very rare – vasculitis.

Disorders of the respiratory system, thorax and mediastinum: infrequently – shortness of breath, rhinitis; very rarely – cough.

Disorders of the digestive system: frequently – feeling of discomfort in the stomach, pain in the upper abdomen, nausea; infrequently – change of stool, diarrhea, dry mucous membrane of the mouth, dyspepsia, vomiting; very rarely – gastritis, gum hyperplasia, pancreatitis.

Hepatic and biliary tract disorders: very rarely – increased activity of “hepatic” enzymes, including increased bilirubin concentration in serum (usually associated with cholestasis), hepatitis, intrahepatic cholestasis, jaundice.

Dermatological and subcutaneous tissue disorders: infrequent – alopecia, exanthema, hyperhidrosis, purpura, skin color changes, photosensitization, skin itching, skin rash; very rare – angioedema (Quincke’s edema), urticaria, erythema multiforme, exfoliative dermatitis, Stevens-Johnson syndrome.

Muscular and connective tissue disorders: frequently – edema of the ankles; infrequently – arthralgia, back pain, muscle spasms, myalgia.

Kidney and urinary tract disorders: infrequent – disorders of urination, nycturia, pollakiuria.

Renital and breast disorders: infrequent – impotence, gynecomastia.

General disorders: frequent – increased fatigue, edema; infrequent – asthenia, discomfort, malaise, noncardiac heart pain, pain of various localization.

Laboratory and instrumental data: infrequently, increase or decrease in body weight.

Valsartan

The following are the NFRs identified in patients with arterial hypertension in clinical trials as well as in clinical practice and laboratory studies. For the NFRs identified in clinical practice and laboratory studies, the frequency of occurrence cannot be determined; therefore, for these NFRs, “frequency unknown” is indicated.

Disorders of the blood and lymphatic system: frequency unknown – decrease in hemoglobin and hematocrit, neutropenia, thrombocytopenia.

Disorders of the immune system: frequency unknown – hypersensitivity reactions, including serum sickness.

Hearing organ and labyrinth disorders: infrequent – vertigo.

Vascular disorders: frequency unknown – vasculitis.

Relatory system, thorax and mediastinum disorders: infrequent – cough.

Disorders of the digestive system: infrequent – abdominal discomfort, pain in the upper abdomen.

Hepatic and biliary tract disorders: frequency unknown – impaired liver function, increased activity of “liver” enzymes, increased plasma bilirubin concentration.

Dermatological and subcutaneous tissue disorders: frequency unknown – angioedema, bullous dermatitis, itching, skin rash.

Musculoskeletal and connective tissue disorders: frequency unknown – myalgia.

Recreational and urinary tract disorders: frequency unknown – increased serum creatinine concentration, renal dysfunction, including acute renal failure.

General disorders: infrequently – increased fatigue, asthenia.

Laboratory and instrumental findings: frequency unknown – increased plasma potassium.

If any of the side effects listed in the instructions worsen, or if you notice any other side effects not listed in the instructions, tell your doctor.

Overdose

There are currently no data on cases of overdose of amlodipine + valsartan combination.

Symptoms:In an overdose of valsartan, development of a marked decrease in BP accompanied by dizziness can be expected. Amlodipine overdose may result in excessive peripheral vasodilation and possible reflex tachycardia. Severe and prolonged systemic arterial hypotension up to and including shock with fatal outcome has also been reported.

The treatment:is symptomatic, the nature of which depends on the time elapsed since taking the drug and the severity of symptoms. If the drug has been taken recently, vomiting or gastric lavage should be induced. The use of activated charcoal in healthy volunteers immediately or within 2 hours after taking amlodipine significantly reduced its absorption. In case of pronounced BP decrease in case of drug overdose, active measures on cardiovascular system support are required, including regular control of cardiac and respiratory system function, transfer patient to “lying” position with elevated legs, it is worth paying special attention to the volume of urine excreted.

In the absence of contraindications, a vasoconstrictor may be used (with caution) to restore vascular tone and BP. Calcium gluconate may be administered intravenously to reverse the effects of BMCC.

Valsartan and amlodipine are unlikely to be excreted by hemodialysis.

Pregnancy use

With regard to the mechanism of action of ARA II, the risk of their use for the fetus cannot be excluded. It is known that the prescription of ACE inhibitors, which affect the RAAS, to pregnant women in the second and third trimesters leads to damage or death of the developing fetus. According to a retrospective analysis, the use of ACE inhibitors during the first trimester of pregnancy was accompanied by the development of fetal and neonatal pathology. Inadvertent use of valsartan in pregnant women has been associated with spontaneous abortions, fetal abnormalities, and renal dysfunction in the newborn.

The combination drug Valz Combi (amlodipine + valsartan), like any other drug with a direct effect on the RAAS, should not be prescribed during pregnancy and in women who wish to become pregnant. Patients of childbearing age should be informed of the possible risks to the fetus associated with the use of drugs affecting the RAAS. If pregnancy is detected during treatment with amlodipine + valsartan combination drug, the drug should be discontinued as soon as possible.

It is not known whether valsartan and/or amlodipine penetrate into breast milk. Since experimental studies have noted excretion of valsartan with breast milk, it is not recommended to use Valz Combi during breastfeeding.

Similarities